The present invention relates generally to targeted therapy and medical imaging as applied to cancer treatment and diagnosis, and in particular to conjugates composed of a radiolabeled, cell cycle-dependent therapeutic agent chemically coupled to a ligand that targets androgen receptor (AR). The conjugates of the invention are taken up selectively by malignant tumor cells that have androgen receptor and are incorporated into the nucleus of such cells, where they produce a cytotoxic effect and/or are detectable via radioimaging techniques.
The main treatments for breast, prostate, ovarian and many other cancers are surgery, chemotherapy and radiation therapy. In some cases a combination of two or more of these treatments is recommended. Typically, clinical trials for advanced carcinomas use combination chemotherapy based on established anti-cancer agents. For example, there are numerous active clinical trials (Phase I) dealing with recurrent and progressive ovarian carcinoma that rely on existing drugs such as paclitaxel, carboplatin, cisplatin, floxouridine and similar drugs in a combination chemotherapy. Many of these include an autologous stem cell support to combat the side effects brought on by the administration of these drugs. Newer drugs include matrix metalloproteinase inhibitors, vaccines, and antibodies.
Many of the currently available front-line and salvage agents used in cancer therapy are associated with cumulative and/or irreversible toxicities that pose challenges for long-term treatment planning. The irreversible effects associated with some of these therapies include development of multidrug resistance, neurotoxicity, and nephrotoxicity. All of these diminish the probability of improved responses when multiple treatments are needed to keep the cancer under control.
It has previously been proposed to use targeted cytotoxic radioisotopes for the treatment and diagnosis of cancer. One of the intended benefits of targeted therapy is to diminish the incidence and severity of side effects by confining toxic exposure, more or less, to the disease site. Certain radioisotopes, particularly Auger electron-emitting isotopes, such as 123I and 125I are known to be very toxic to viable cells, but only if they are localized within the nucleus of the cell. (Warters et al., Curr. Top. Stop Rad. Res., 12:389 (1977).) It has been reported that 5′-iodo-2′-deoxyuridine (IUdR), when labeled with the Auger electron emitter 123I or 125I exhibits substantial toxicity in mammalian cells in vitro (Makrigiorgos et al., Radiat. Res., 118:532–44 (1989)) and produces a therapeutic effect in animal tumor models (Baranowska-Kortylewicz et al., Int. J. Radiat. Oncol. Biol. Phys., 21:1541–51 (1991)). Furthermore, radiolabeled IUdR has been found to enable scintigraphic detection of animal and human tumors (Baranowska-Kortylewicz, supra). See also U.S. Pat. Nos. 5,094,835 and 5,308,605.
Considerable effort has been devoted to developing antibodies for the targeted delivery of therapeutic and diagnostic agents. However, antibodies themselves have not been capable of reaching the cell nucleus in effective amounts. Most such antibodies react with the cell surface, and are gradually internalized, routed to lysosomes and degraded (Kyriakos et al., Cancer Res., 52:835 (1992)). Degregation products, including any radioisotopes attached thereto, then gradually leave the cell by crossing the lysosomal membrane and then the cell membrane. Although a conventional radioisotope label on an antibody degradation product can theoretically pass through the nuclear membrane and deliver some radioactivity to the nucleus (Woo et al., WO 90/03799) actual observations show that the amount is limited, and in any event, is insufficient to have a toxic effect on tumor cells.
Protein and polypeptide hormones and growth factors, particularly those having cell surface receptors, may be directly radiolabeled and used to target a tumor cell. As in the case of targeting radiolabeled antibodies, however, radioisotopes bound to amino acid residues of hormones, growth factors and the like exit from the cell after catabolism, and do not appreciably bind to nuclear material.
Despite the many advances in the field of cancer therapy and diagnosis, there remains an acute need for innovative treatment methods, particularly for cancers having high instances of relapse, which can be safely applied in a repetitive, long-term regimen, without the side effects produced by existing treatments.